title: The design, synthesis, and anti-tumor mechanism study of N-phosphoryl amino acid modified resveratrol analogues.
abstract: A novel series of trans-N-phosphoryl amino acid modified resveratrol analogues were synthesized and evaluated in vitro for their cytotoxic effects against CNE-1 and CNE-2 cell lines. These analogues showed good anti-proliferative activity, among which 8d, 8e, 8j, and 9d displayed much stronger inhibition effect than resveratrol and 8d showed the most potent activity with IC(50) value at 3.45+/-0.82microM. The anti-tumor effects of 8d, 8e, 8j, and 9d were due to the induction of apoptosis, confirmed by the DNA fragmentation and flow cytometry analysis using PI (propidium iodide) staining and Annexin-V-FITC/PI staining assay. The PI staining assay also showed that 8d, 8e, 8j, and 9d caused cell cycles arrest at G(0)-G(1) phase which finally led to cell apoptosis. Further mechanism study on compound 8d against CNE-2 cells has shown the PARP cleavage, which is a hallmark of caspase-3 activation, as well as the activation of caspase-9, and the intracellular ROS generation. These results all suggest that 8d induced a mitochondrial-dependent apoptosis pathway.
authors.affiliation: Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology, Ministry of Education, Department of Chemistry, Tsinghua University, Beijing 100084, China.
authors.forename: Huachen
authors.initials: H
authors.lastname: Liu
authors.forename: Aijun
authors.initials: A
authors.lastname: Dong
authors.forename: Chunmei
authors.initials: C
authors.lastname: Gao
authors.forename: Chunyan
authors.initials: C
authors.lastname: Tan
authors.forename: Hongxia
authors.initials: H
authors.lastname: Liu
authors.forename: Xuyu
authors.initials: X
authors.lastname: Zu
authors.forename: Yuyang
authors.initials: Y
authors.lastname: Jiang
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism; D053938:DNA Fragmentation; D006367:HeLa Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D019606:Phosphoamino Acids / Q000737:chemistry*; D000077185:Resveratrol; D013267:Stilbenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D019606:Phosphoamino Acids; D013267:Stilbenes; D020169:Caspases; D000077185:Resveratrol